BAFF-R (also called BR3, TNFRSF13C or CD268) is a tumor necrosis factor (TNF) receptor superfamily member expressed predominantly on mature B-lymphocytes and on a subset of T-cells (L. G. Ng, et al., J Immunol, 173 (2004), pp. 807-817. BAFF-R and two other TNF superfamily receptors called TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and BCMA (B-cell maturation antigen), are expressed mainly on B lymphocytes and their expression varies as a function of B cell maturation. Each specifically binds a ligand called B-Lymphocyte stimulator (BAFF; also referred to as BLyS, CD257, TALL-1, THANK, TNFSF13B or ZTNF4) which is expressed in myeloid cells and a variety of other cell types. While BCMA and TACI also interact with other ligands, BAFF-R is reportedly exclusive to BAFF. Each of the three TNF receptors has a different binding affinity for BAFF. BAFF trimerizes and binds to cell surface BAFF-R, upon which the complex is internalized by receptor-mediated endocytosis.
The BAFF/BAFF-R interaction has been shown to be significant in B-cell survival, maintenance and proliferation. Functionally, the BAFF/BAFF-R interaction is critical for maturation of immature transitional B-cells and for survival, migration and activation of mature B-cells including isotype class switching. BAFF can act alone or in concert with other agents, e.g., B-cell receptor (BCR), interleukin-4, interleukin-21 or CD40 ligand.
BAFF antagonists may have therapeutic benefit for treating autoimmune diseases in which B cells play a pathogenic role. Overproduction of BAFF can trigger severe autoimmune disorders in mice resembling systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS) (Ju et al., Immunol. 2007 120(2):281-9). Increased levels of BAFF are also found in human patients suffering from SLE, SS, rheumatoid arthritis (RA), Wegener's granulomatosis and certain B-cell malignancies. Moreover, in animal models of autoimmune disease, such as SLE, rheumatoid arthritis (e.g., collagen-induced arthritis) and multiple sclerosis (e.g., experimental autoimmune encephalomyelitis), the disease phenotype can be partially reverted by treating with soluble BAFF-R-Fc fusion proteins that bind to BAFF thereby antagonizing BAFF/BAFF-R interaction. Treatment with BAFF-R-Fc fusion proteins has also been shown to inhibit chronic graft-versus-host disease (cGVHD) by blocking B-cell survival. And, anti-BAFF antibodies are clinically beneficial when administered to rheumatoid arthritis or SLE patients, establishing a nexus between BAFF antagonism and therapeutic efficacy in these autoimmune disorders.
A variety of B-cell malignancies show increased expression of BAFF-R. Different Non-Hodgkin's Lymphoma (NHL) cell lines, for example, express BAFF-R to different degrees. The BAFF/BAFF-R interaction also increases the survival and proliferation of malignant cells, enabling cancer cells to proliferate faster than normal B-cells. Because BAFF-R is thought to be the only receptor that mediates the B cell survival signal from BAFF, agents that modulate BAFF/BAFF-R interaction could be useful treatments for various B cell malignancies.
Accordingly, BAFF-R, as the predominant BAFF receptor expressed on B cell lines, is thought to represent an attractive target for therapeutic intervention in B cell malignancies such as lymphomas and in autoimmune diseases involving B cells. To that end, a number of B-cell targeting therapeutic antibodies have been developed, the earliest ones directed to CD20 (e.g., rituximab, a chimeric mouse/human IgG1 approved for hematological cancers and refractory RA; ofatumumab, a human IgG1 approved for refractory chronic lymphocytic leukemia “CLL” and in clinical trials for other hematological cancers, including relapsing remitting multiple sclerosis “RRMS”; and ocrelizumab, a humanized IgG1 in clinical trials for RRMS). Epratuzumab is a humanized mouse monoclonal antibody directed to CD22, currently in clinical trials for systemic lupus erythematosus “SLE” and Non-Hodgkin's Lymphoma “NHL”. Certain human anti-BAFF antibodies have been developed, including belimumab (human IgG1) and blisibimod (human IgG4), which are approved and/or in clinical trials for treatment of SLE and various other indications. See, e.g., WO2011/160086; WO2006/025345; WO2003/016468; and WO2000/043032.
Monoclonal antibodies have revolutionized biotechnology and are now key therapeutic drugs in the treatment of human disease. Despite their successes, therapeutic monoclonal antibodies have certain limitations, such as restricted activity against certain types of antigen, poor tissue penetration, unwanted effector function in many situations, the cost of manufacturing, product instability and aggregation. Single domain antibodies that occur naturally in the shark are particularly attractive for the development of next generation biotherapeutics. VNARs are small (12 kDa), stable, soluble, monomeric antigen-binding domains that can be configured into many different therapeutic modalities. The isolation of various VNAR based binding moieties has been described. See, e.g., WO2003/014161 and WO2005/118629.
It would be desirable to have additional BAFF antagonists, especially ones having one or more advantageous biological properties with therapeutic and/or diagnostic benefit over current anti-BAFF antibodies.